DE1210818B - Process for the preparation of 1,1-ethylene-17alpha-alkyl-delta 2-5alpha-androsten-17beta-ols and their 17-esters - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

Number:
File number:
Registration date:
Display day:

C07c

German class: 12 ο - 25/04

Sch34562IVb / 12o
February 1, 1964
17th February 1966

The invention relates to a process for the preparation of l, l-ethylene-17a-alkyl- ^ ² -5a-androstene-HjS-ols and their esters of the general formula

OR ¹

where R ^{1 is} hydrogen or an acyl radical and R ^{2 is} a saturated or unsaturated lower alkyl radical, in particular the methyl, ethyl, ethynyl or vinyl radical.

The process according to the invention consists in that, in a manner known per ^{se, a 17a alkyl group is introduced into 1,1-ethylenzl 2} -5a-androsten-17-one either by Grignardation or a process for the preparation of 1,1-ethylene-17a alkyl-z / ² -5a-androstene-17 / S-ols and their
17 esters

Applicant:

Schering Aktiengesellschaft,

Berlin 65, Mullerstr. 170/172

Named as inventor:

Dr. Hans Müller,

Dr. Friedmund Neumann, Berlin;

Dr. Rudolf Wiechert ,. Berlin-Wannsee

followed by an analogously introduced 17a-ethynyl group reduced to vinyl or ethyl group:

H ₂ C - CH ₂

H ₂ C - CH ₂

CH = CH ₂

Depending on the desired meaning of R ¹ , this is then optionally followed by an esterification of the primary esterification. Steroid alcohols with the desired acid or a reactive acid derivative thereof. Acids are to be understood here as meaning all acids commonly used in steroid chemistry for the esterification of steroid alcohols.

As a starting material of the invention

Process serving 1,1-ethylene-zl ² -5a-androsten-17-one not previously described in the literature can

according to methods known per se from 1-methyl-

609 508/316

e.g. produced according to the following reaction scheme:

CH;

OH

CH ₂

HO • CH ₂ • CH ₂ • OH

P-TsOH ₁ [-0

OH

J • CH ₂ • J
Zn, Cu

Py, Ac ₂ O

OH

OAc

CH ₃ OH

H ₂ SO ₄

NaBH ₄

M.p. 168 to 169 ° C HO

OH

M.p. 136-137 ° C OAc

3a- + 3/3-epimer mixture

OAc OAc '

Pv, p-TsCl,

Tos —O

CH ₃ OH, K ₂ CO ₃ ,

BzI, Al ₂ O ₃

146.5 to 147 ° C OH

CrO ₃

83 to 86 ° C

F. 107 to 109 ⁰ C

For the production of the starting material, protection is not given in the context of the present invention desired.

The novel 1,1-ethylene-17a-alkyl-zl ² -5a-androstene-17/3-ols that can be prepared according to the invention and their 17-esters are valuable pharmaceuticals.

The l, l-Ethylene-17a-methyl-zl ² -5a-androsten-17 / S-ol is a highly effective anabolic perorally without any noteworthy androgenic side effects. Its peroral anabolic and androgenic efficacy was compared using standard methods on the castrated male rat in the levator ani test and in the seminal vesicle test with the corresponding effects of the standard substance 17a-methyltestosterone and some known anabolic steroids.

Levator Seeds 25th 49 Substance: 12 3 mg ρ. ο. ani bladder 40 88 Weight in mg / 100 g rat 26th 28 17a-methyltestosterone 4-hydroxy-17ct-methyltestosterone 34 34 17a-methylpyrazolo- [3,2-c] - 5a-androstane-17 ^ -ol .-. l, l-ethylene-17a-methyl- Zl ² -5a-androsten-17 ^ -ol

From the table above it is clear that the new substance is not just opposite the 17a-methyltestosterone the advantage of a significantly increased anabolic effectiveness and a has decreased androgenic effects, but also against well-known and proven anabolic steroids shows better dissociation of these effects or an absolute increase in effectiveness.

In addition to the anabolic activity mentioned, the l, l-ethylene-17a-alkyl- / l ² -5a-androstene-17 / S-ols and their 17-esters according to the invention have a strong ovulation-inhibiting activity. Compared with known ovulation inhibitors such as 17a-ethynyl-19-nor-testosterone and its 17-acetate, l, l-ethylene-17a-methyl-, d ² -5a-androsten-17jS-ol was found when administered orally to normal female rats three times stronger. For this determination, the ovulation that took place or that did not occur was determined by inspection of the tube. The table below specifies that dose (WD50) after which 50% of the animals did not ovulate after oral administration.

substance WD50 P- O.
mg / animal / day
(For 4 days) Ha-ethynyl-W-nor-testosteron ....
17a-ethynyl-19-nor-testosterone-
17-acetate 3
3 l, l-ethylene-17a-methyl-
zJ ² -5a-androsten-17 /? - ol 1

example 1

To the cooled Grignard solution, made from 4.49 g of magnesium shavings in 50 ml of absolute ether and 11.6 ml of methyl iodide in 32.4 ml of absolute ether, 4.1 gl, l-ethylene- / l ² -5a-androsten-17- on (IX) in 148 ml of absolute benzene was added dropwise and the mixture was stirred for 4 hours at room temperature under nitrogen. Then concentrated aqueous ammonium chloride solution is carefully added with external cooling with ice, it is weakly acidified with dilute hydrochloric acid and extracted with ether. The ethereal phase is washed neutral, dried and evaporated. The residue is chromatographed over silica gel. Eluting with carbon tetrachloride-methylene chloride (1: 1 and 1: 3) gives 3.36 g of 1,1-ethylene-17a-methyl-zl ² -5a-androstene-17 _l ö-ol with a melting point of 125 bis 126 ⁰ C.

Example 2

The cooled Grignard reagent made from 6.08 g of magnesium turnings in 75 ml of absolute tetrahydrofuran and 19 ml of ethyl bromide in 75 ml of absolute tetrahydrofuran is added to 90 ml of absolute tetrahydrofuran through which acetylene has previously been passed for 20 minutes. The temperature rises to 45 ^° C. during this process. Acetylene continues to be passed in until the temperature falls again. Then 3 gl, l-ethylene-z! ² -5a-androsten-17-one (IX) in 75 ml of absolute tetrahydrofuran was added dropwise. Acetylene is still being introduced during the dropwise addition. Then the reaction mixture under nitrogen and with stirring 21 hours in 7O ⁰ C hot oil bath heated.

After cooling to 5 ^° C., concentrated aqueous ammonium chloride solution is slowly added until no further reaction occurs. It is then extracted with ether, the organic phase washed neutral with water, dried over sodium sulfate, evaporated to dryness in vacuo and the residue chromatographed over silica gel.

Eluting with carbon tetrachloride-methylene chloride (2: 1) gives 1.31 g of 1,1-ethylene-17a-ethinyl- A ² - 5a - androsten - Yl β - oil as an oil; [a] f = + 60 ° (CHCl ₃ ; c = 1).

For example 3

325 mg of 1,1-ethylene-17a-äthinyl- ^ ² -5a-androsten-17jS-ol prepared according to Example 2 are dissolved in 30 ml of pyridine and, with the addition of 60 mg of 5% palladium-carbon catalyst, are absorbed 1 mmol hydrogen hydrogenated. The catalyst is then filtered off and the solution is concentrated to dryness in vacuo. The residue is taken up in ether, the ether phase is washed with 1N hydrochloric acid and water, dried over sodium sulfate and evaporated. There remain behind 240 mg l, l-ethylene-17a-vinyl-z) ^{2-5a-androsten-17jS-ol,} m.p. 78 to 81.5 ⁰ C.

Example 4

To the cooled Grignard solution, prepared from 3.94 g of magnesium shavings in 44 ml of absolute ether and 10.2 ml of ethyl iodide in 28.4 ml of absolute ether, 3.46 g of l-ethylene-zl ² -5a-androsten-17-one are added (IX) was added dropwise in 130 ml of absolute benzene and stirred for 7 hours at room temperature under nitrogen. Then, with external cooling with ice, first concentrated aqueous ammonium chloride solution and then dilute hydrochloric acid are added until the reaction is weakly acidic.

The organic phase is separated off and the aqueous phase is extracted with ether. After washing until neutral, drying and evaporation of the combined organic phases, the residue is chromatographed over silica gel with carbon tetrachloride-methylene chloride (2: 1). This gives 1.05 g U-ethylene-na-ethyl - ^ - Sa-androstene-n / S-ol, F. 117 to 118.5 ⁰ C.

Example 5

1,1-ethylene-17a-methyl-zl ² -5a-androsten-17 / S-ol, 5 ml of pyridine (absolute) and 5 ml of acetic anhydride are heated to 130 to 140 ° C. for 4 hours . The reaction mixture is then stirred into ice-cold sodium chloride solution, filtered off and washed neutral with water. The dark brown precipitate is recrystallized twice from isopropyl ether over charcoal. 630 mg of l, l-ethylene-17a-methyl-zl ² -5a-an-

Claims (1)

8th drosten-HjS-ol-n-acetate with the melting point where R ^{1 is} hydrogen or an acyl radical and M.p. 130.5 to 131.5 ° C as colorless crystals. R ^{2 is} a saturated or unsaturated lower one Alkyl radical, especially the methyl, ethyl, Claim: Ethynyl or vinyl radical, means thereby Process for the preparation of 1,1-ethylene-5 characterized in that one in itself 17a-alkyl-zl ² -5a-androstene-17/9-ols and their known manner in l, l-ethylene-zl ² -5a-androstene- 17-esters of the general formula 17-one either by Grignardation _OR1 . 17a-position alkyl group introduces or a ι analogously introduced 17a-ethynyl group then ^ - R ² 10 ßend reduced to the vinyl or ethyl group and, depending on the desired meaning of R ^1, optionally subsequently esterifying the steroid alcohols formed primarily with the desired acid or a reactive acid derivative of the acid in question. 508/316 2.66 © Bundesdruckerei Berlin